Project Summary Abstract The focus of this proposal is to characterize DAergic modulation of coarse and fine locomotor control using a multi-level integrative approach, from behavior to receptor signaling, that employs a powerful array of approaches. To gain a fundamental understanding of the cellular, network and modulatory properties that underlie the development of vertebrate locomotor activity it is critical to examine the neural mechanisms that drive the activity. This proposal is designed to address three main points: 1) Determine the neural mechanisms underlying a developmental switch in locomotor activity from an immature to a mature pattern by a combination of pharmacological, optogenetic and calcium imaging experiments, 2) Characterize the role of descending dopaminergic drive in fine motor behaviors, such as orienting and advancing maneuvers during hunting, by high-speed kinematic analysis of larvae with targeted inactivation (laser photoablation and/or optogenetic) of dopaminergic neurons in the ventral diencephalon, and 3) Identify spinal neurons modulated by the descending dopaminergic drive by correlating the expression of dopamine receptor mRNA transcripts with identified classes of putative locomotor-related spinal neurons. The broad intellectual scope of this proposal and the use of diverse experimental techniques, from simple behavioral measurements to the optical control of neuronal activity, permit the inclusion of students across various levels of sophistication, including high school (restricted to summer months), undergraduate and graduate students, and postdoctoral associates. The lab currently has one graduate student, one post-doctoral associate (5+ years of experience), a senior research associate (over 20+ years of experience), and several undergraduates. Understanding the cellular, network and modulatory properties that underlie the development of locomotor activity will likely aid in developing therapeutic interventions for DAergic-related diseases of the motor system, such as Restless Leg Syndrome, Periodic Leg Movement Disorder and Parkinson's Disease.